Foamy virus-host interactions

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Foamy viruses (FV) are retroviruses but, unlike the orthoretroviruses, have no disease association. The studies reported in this dissertation address foamy virus-host interactions in order to understand why foamy virus infection is nonpathogenic. I evaluate hypotheses that could explain this apparent anomaly, namely, that viral latency or the host immune system limits potential pathogenic effects. Utilizing naturally FV-infected rhesus macaques (Macaca mulatta ), I determined that viral replication in hosts is limited to the oropharyngeal tissues. Further, I found that FV infection is not characterized by latency, and that robust viral replication is detectable in the oral cavity, with the highest levels in samples obtained from oral swabs. Surprisingly, host immune responses, which are characterized in this research, do not contribute significantly to limiting viral replication in the blood or other tissues. This was most convincingly demonstrated by the utilization of simian immunodeficiency virus (SIV)-infected macaques that were severely immunosuppressed and depleted of CD4+T cells. In these SIV-infected macaques, there was an expansion of FV replication to only one tissue---the jejunum---and not to any other tissues that were also highly depleted of CD4+T cells. Thus, systemic immune control of FV infection appears to be insignificant, and it is likely that SIV-induced changes unique to the jejunum account for FV replication there. Finally, I identified the cell type that is permissive for FV replication in vivo: superficial epithelial cells in the outermost layers of the oral mucosal epithelium, many of which appeared to be actively shedding. This cellular site of replication offers a plausible explanation of the innocuous character of FV infection, since this cell type turns over rapidly and is relatively dispensable to its host. Limitation of viral replication to a superficial site is likely to minimize damage to its host while increasing the efficiency of virus transmission via shed cells in saliva. Taken together, these findings have contributed to an explanation of the nonpathogenic outcome of FV infection and allowed for the development of a model of within-host spread of FV infection.